Guilherme Godoy

INTRODUCTION

Penile cancer is a rare malignancy that involves the squamous mucosal epithelia of the glans, coronal sulcus, and inner prepuce, potentially extending to the corpora, urethra, and penile shaft in more advanced stages. Tumors arising from the mid and proximal penile shaft skin are extremely uncommon.

It affects men in their fifties, with peak incidence between the ages of 50 and 70 years. Cancer of the penis is associated with significant morbidity and mortality with important impact in both sexual and urinary functions and potentially devastating psychologic consequences to the patients (1,2).

The overall 5-year cancer-specific survival is approximately 50%, ranging from 85% to 29%-40% in those without and with lymph node metastasis, respectively, down to <10% in those with pelvic lymph node involvement (3, 4).

It represents 0.4% to 0.6% of all malignant tumors among men in the United States and Europe, with an average reported incidence of 1:100,000 men per year in the United States (2, 5). In 2017, 2,120 new cases are estimated, with 360 expected deaths from this disease in the United States (6). The incidence is variable according to the geographical region. The highest rates are in some developing countries of Asia, Africa, and South America, where penile cancer comprises up to 20% of all malignancies (7).

The most common histological type is the conventional squamous cell carcinoma (SCC), which comprises approximately 95% of all penile cancers, but several other morphological subtypes and variants exist. Table 33.1 illustrates the variable histopathological presentations of these lesions with their respective prognosis (8).

Several premalignant lesions are also recognized. Appropriate diagnosis and treatment of these lesions are important to prevent the development of invasive tumor stages. Table 33.2 illustrates the main described premalignant lesions (8).

The primary lesion follows a progressive and local pattern of growth and infiltration in the penis, invading deeply from the skin to the corpora and urethra. Metastatic spread occurs predominantly via lymphatic dissemination in a stepwise fashion, starting from the superficial to the deep inguinal lymph nodes before reaching the pelvic lymph nodes and other organs. Therefore, early diagnosis and treatment are key to successful management of the disease.

Although surgical excision is the mainstay of the treatment of the early forms of the disease, a multimodal approach with the integration of radiation and chemotherapy is critical to appropriate management of more advanced stages of this disease.

RISK FACTORS

The presence of phimosis and uncircumcised foreskin is an important and very well described risk factor associated with the development of penile cancer. The lifetime risk of developing penile cancer in uncircumcised American men is estimated to be 1:400, compared to 1:100,000 in circumcised men. Especially when performed in the prepubertal phase, there is a 22-fold risk reduction associated with circumcision. The benefit in penile cancer prevention seems to be maximized when it is performed in the neonatal period. In countries where most circumcisions are performed in newborns, the reported incidence rates are lower than 0.1:100,000 men (9). Furthermore, among 50,000 cases and 10,000 deaths from penile cancer occurring between 1930 and 1990, only 10 were documented in circumcised patients, all of whom underwent circumcision after puberty (10).

Other important described risk factors that are associated with the presence of phimosis or uncircumcised foreskin in most cases are balanitis, balanoposthitis, chronic 254inflammatory conditions (lichen sclerosus or balanitis xerotica obliterans), poor genital hygiene (accumulation of smegma), and lower socioeconomic status.

The history of sexually transmitted diseases, especially HIV and human papillomavirus (HPV) infection, is also an important risk factor. In general, the majority (up to 80%) of penile cancers are related to HPV infection, specifically the serotypes 16 and 18 (highest association), and also 31, 33 and other serotypes (1,2,11–13).

Uncircumcised men have a 5 to 10 times higher chance of acquiring HPV infection. This association is probably the most important association of factors (uncircumcised foreskin and HPV infection) for the development of the disease. HIV infection has also been reported to increase the risk of penile cancer by 8 fold (14).

Other risk factors include cigarette smoking, which is reported to increase the risk of developing penile cancer by 3 to 4.5 times, and the exposure to psoralen plus ultraviolet A radiation, a form of photochemotherapy used for the treatment of a variety of skin conditions, including psoriasis, vitiligo, and eczema.

DIAGNOSIS AND STAGING

The most common presentation is the presence of a sessile and painless penile tumor involving the glans and/or inner prepuce, or a palpable mass underlying the uncircumcised foreskin.

It can be associated with pain, discharge, bleeding, and foul odor, if secondarily infected or with presence of necrotic areas in more advanced lesions. At later stages, patients can present with palpable or ulcerated inguinal nodal metastasis and even constitutional symptoms.

The lesion itself can be characterized as nodular, ulcerative, or fungating. However, early stages may be more subtle, presenting just as discoloration, plaques, or small skin ulcers. Any lesion that does not heal after a short period of monitoring for 2 to 3 weeks with proper hygiene and skin care should be biopsied.

Tables 33.1 and 33.2 list the different types of histologic variations and the recognized premalignant lesions, also known as penile intraepithelial neoplasia (PeIN), illustrating the different possible presenting forms of the disease.

255Biopsy is the mainstay of histopathological diagnosis. Its extent should take into consideration the location of the lesion and assess depth of invasion for staging purposes. The biopsy will also inform important risk factors, such as the histologic subtype, presence of lymph vascular invasion, and the degree of cell anaplasia (classifying the tumors according to their differentiation status).

In small and superficial lesions, an excisional biopsy may be both diagnostic and therapeutic. Tumors confined to the prepuce are perfect examples of such lesions that can be managed with a circumcision.

Physical exam of the bilateral inguinal lymph nodes is critical for proper staging. The use of ultrasonography and axial imaging (CT or MRI) may aid in further characterization and staging of both the primary tumor and inguinal lymph nodes. Information such as number of involved lymph nodes, location, size, and mobility are meaningful for decision-making. These need to be assessed bilaterally at presentation and at every visit during follow-up in those cases under surveillance. Complete staging for invasive tumors should also include imaging of the chest, abdomen, and pelvis (usually starting with a chest x-ray and CT of abdomen and pelvis).

Recently, the use of positron emission tomography scan (PET) with CT scan has been very useful in the diagnosis of regional metastatic disease (15, 16).

The staging system most commonly used in penile cancer is the American Joint Commission on Cancer (AJCC) tumor, node, and metastasis (TNM) system (Table 33.3) (17).

 

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Table 33.3 Penile Carcinoma TNM Staging System

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Primary Tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Ta	Noninvasive localized squamous cell carcinoma
Tis	Carcinoma in situ (Penile intraepithelial neoplasm [PeIn])
T1a	Tumor invades subepithelial connective tissue without lymph vascular or perineural invasion and is not poorly differentiated
256T1b	Tumor invades subepithelial connective tissue with lymph vascular or perineural invasion or is poorly differentiated
T2	Tumor invades corpus spongiosum with or without urethral invasion
T3	Tumor invades corpora cavernosum with or without urethral invasion
T4	Tumor invades into adjacent structures (i.e., scrotum, prostate, pubic bone)
Regional Lymph Nodes (N)
cNX	Regional lymph nodes cannot be assessed
pNX	Lymph node metastasis cannot be assessed.
cN0	No palpable or visibly enlarged lymph node metastasis
pN0	No lymph node metastasis
cN1	Palpable mobile unilateral inguinal lymph node
pN1	Metastasis in ≤2 unilateral inguinal nodes, no extracapsular extension
cN2	Palpable mobile ≥2 unilateral or bilateral inguinal lymph node metastases
pN2	Metastasis in ≥3 unilateral or bilateral inguinal lymph node metastases
cN3	Palpable fixed inguinal nodal mass or pelvic lymphadenopathy unilateral or bilateral
pN3	Extranodal extension of lymph node metastasis or pelvic lymph node metastasis
Distant Metastasis (M)
M0	No distant metastasis
M1	Distant metastasis

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